The present invention relates to a pyrimidine nucleus-containing compound such as a thienopyrimidine derivative or a quinazoline derivative which is useful for pharmacotherapeutically ameliorating arterial blood oxygen partial pressures (PaO2) in hypoxemic patients and those patients who are under oxygen inhalation treatment due to acute respiratory insufficiency.
While broncodilators, antiphlogistics, cardiac insufficiency treating agents, antitussives, etc. have been used currently as neosotropic agents for treating respiratory insufficiency diseases, there is no effective medicaments for patients suffering from hypoxemia such as chronic obstructive pulmonary disease (COPD).
Under such circumstances, medicaments for enhancing and ameliorating PaO2 values caused to be lowered by respiratory diseases have been in demand. Further, these diseases are often accompanied by increase in the arterial blood CO2 partial pressure (PaCO2) in addition to drop in PaO2, and in such cases medicaments having PaCO2 lowering actions in addition to PaO2 enhancing actions have been necessitated.
The present inventors made intensive studies in search of medicaments which ameliorate blood oxygen partial pressure in hypoxemia to find that a pyrimidine nucleus-containing compound such as a thienopyrimidine derivative or a quinazoline derivative to be described later is useful for prophylaxis and therapy of hypoxemia incidental to respiratory diseases.
The compound of the present invention has actions to enhance respiratory functions in the lungs and to increase PaO2 by redistribution of bloodstream based mainly on hypoxemic pulmonary vasoconstriction (HPV) enhancing actions or to increase ventilation and respiration rate whereby to increase PaO2 and also to reduce PaCO2.
The compound of the present invention relates to a pyrimidine nucleus-containing compound represented by the formula (I): 
wherein ring A represents the ring of the formula (a): 
in which R1 is a nitro group, an amino group, a substituted amino group or a halogen atom, or the ring of the formula (b): 
in which R1xe2x80x2 is an alkyl group, an alkenyl group, a phenyl group, a nitro group, an amino group, a substituted amino group or a halogen atom;
R2 and R4 independently represent a hydrogen atom, an alkyl group or an alkenyl group; and
R3 and R5 independently represent an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a cycloalkyl group, an adamantyl group, a pyridylmethyl group, a furylmethyl group, a thienylmethyl group, a cinnamyl group, an acyl group, an alkoxycarbonyl group, a substituted alkyl group, a substituted carbamoyl group or a substituted amino group; or
either R2 and R3 or R4 and R5, together with the nitrogen atom to which they are attached, may form a 4 to 7-membered saturated heteromonocyclic ring which may be substituted;
with the proviso that at least one of R2 to R5 is an alkenyl group,
or acid addition salts thereof.
That is, the pyrimidine nucleus-containing compound of the present invention relates to a quinazoline derivative represented by the formula (II): 
or acid addition salts thereof, or a thienopyrimidine derivative represented by the formula (III): 
or acid addition salts thereof.
The alkyl group by which ring A (R1xe2x80x2) may be substituted may preferably be a C1-C6 alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl and n-hexyl. In particular, R1xe2x80x2 may preferably be methyl, ethyl or propyl substituting at the 7-position of the thienopyrimidine ring.
The alkenyl group by which ring A (R1xe2x80x2) may be substituted may preferably be a C3-C6 alkenyl group, for example, allyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 4-pentenyl, cis-2-pentenyl, trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl and 1,4-pentadien-3-yl.
The substituted amino group by which ring A (R1, R1xe2x80x2) may be substituted may preferably be a mono- or di-C1-C3 alkylamino group, for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino or mono- or diallylamino.
The halogen atom by which ring A (R1, R1xe2x80x2) may be substituted includes a fluorine, chlorine, bromine or iodine atom.
The alkyl group regarding R2 to R5 may preferably be a C1-C20 alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl and n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
The alkenyl group regarding R2 to R5 may preferably be C3-C6 alkenyl group, for example, allyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 4-pentenyl, cis-2-pentenyl, trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl and 1,4-pentadien-3-yl.
With respect to the substituent group regarding R3 and R5, the alkynyl group includes, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 2-heptynyl; the aralkyl group includes, for example, benzyl, phenetyl, 1-naphthylmethyl and 2-naphthylmethyl, preferably benzyl; the cycloalkyl group, which may preferably be a C3-C6 cycloalkyl group, includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the adamantyl group includes, for example, 1-adamantyl, 2-adamantyl; the pyridylmethyl group includes, for example, 2-pyridylmethyl and 3-pyridylmethyl; the furylmethyl group includes, for example, furfuryl and 3-furylmethyl; the thienylmethyl group includes, for example, 2-thienyl and 3-thienylmethyl; the acyl group, which may preferably be a C1-C6 aliphatic acyl group, includes, for example, formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl; the alkoxycarbonyl group, which may preferably be a C1-C6 alkoxycarbonyl group, includes, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2-methylpropyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; the substituted alkyl group includes, for example, alkoxy-, amino-, carbamoyl-, hydroxy- or halo-substituted alkyl, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-ethylcarbamoyl)propyl, 2-(N-allylcarbamoyl)ethyl, 2-(piperazinocarbonyl)ethyl, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl; the substituted carbamoyl group, which may preferably be a C1-C9 linear alkyl- or alkenyl-carbamoyl, a C3-C8 cycloalkyl- or cycloalkenyl-carbamoyl, an arylcarbamoyl or a heteromonocyclic ring-containing carbamoyl group, includes, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, t-butylcarbamoyl, n-butylcarbamoyl, nonylcarbamoyl, cyclohexylcarbamoyl, allylcarbamoyl, 1-pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-thiomorpholinocarbonyl; and the substituted amino group, which may preferably be a mono- or di-C1-C6 alkyl-amino group or a heteromonocyclic ring containing amino group, includes, for example, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, heptylamino, dimethylamino, diethylamino, dipropylamino, 1-pyrrolidino, piperidino, morpholino, 1-thiomorpholinyl. substituted amino group, which may preferably be a mono- or di-C1-C6 alkyl-amino group or a heteromonocyclic ring-containing amino group, includes, for example, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, heptylamino, dimethylamino, diethylamino, dipropylamino, 1-pyrrolidino, piperidino, morpholino, 1-thiomorpholinyl.
The 4 to 7-membered saturated heteromonocyclic ring formed by R2 and R3 or R4 and R5 together with the nitrogen atom to which they are attached includes, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, piperazino, morpholino and 1-thiomorpholinyl, which may be substituted on the rings with lower alkyl groups such as methyl, ethyl and propyl, a benzyl group, a naphthylmethyl group, a benzhydryl group and a 4,4xe2x80x2-difluorobenzhydryl group.
The acid addition salts include inorganic acid salts such as of hydrochloric acid and sulfuric acid and organic acid salts such as of acetic acid, propionic acid, citric acid, maleic acid, tartaric acid, methanesulfonic acid and p-toluenesulfonic acid.
The pyrimidine nucleus-containing compound represented by the formula (I) can be synthesized by the method which comprises the steps of:
a) reacting a 2,4-dione compound represented by the formula: 
wherein ring A is the same as defined above,
with a halogenating reagent in the presence of a base to prepare a 2,4-dihalo compound represented by the formula: 
wherein X is a halogen atom,
b) reacting said 2,4-dihalo compound with an amine derivative represented by the formula: 
wherein R2 and R3 are the same as defined above,
to prepare a 2-halo-4-amino compound represented by the formula: 
c) reacting said a 2-halo-4-amino compound with an amine compound represented by the formula: 
wherein R4 and R5 are the same as defined above, to prepare said compound of the formula (I).
In particular, the quinazoline derivative of the formula (II) can be synthesized according to a method as shown by the following reaction scheme: 
In Step 1, a quinazolidione derivative (II) is reacted with a halogenating reagent (III) in the presence of a base to prepare a 2,4-dihaloquinazoline derivative (IV). The starting material quinazolidione derivative (II) can be prepared easily by reacting 2-aminobenzoic acid, which may be substituted, with urea (J. Med. Chem., 1995, 38, 2763-2773). As the halogenating reagent, there may be employed phosphorus oxychloride, phosphorus pentachloride or thionyl chloride; while an organic base such as N,N-dimethylaniline, N,N-diethylaniline, triethylamine, pyridine and collidine is employed as the base. The reaction can be carried out in the absence of solvents or in the presence of an inert solvent at 50 to 200xc2x0 C.
In Step 2, the 2,4-dihaloquinazoline derivative (IV) is reacted with an amine derivative (V) to prepare a 2-halo-4-aminoquinazoline derivative (VI). The reaction can be carried out in an inert solvent such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, dimethylsulfoxide (DMSO) and chloroform at xe2x88x9278 to 100xc2x0 C. Besides such organic bases, the reaction may be employed in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium methoxide and potassium t-butoxide.
In Step 3, the 2-halo-4-aminoquinazoline derivative (VI) is reacted with an amine derivative (VII) to prepare a quinazoline derivative (I). The reaction can be carried out in the absence of solvents or in the presence of the above-mentioned inert solvent at 0 to 250xc2x0 C. An addition of the organic base or the inorganic base as mentioned above is preferable in order to carry out the reaction efficiently.
The thienopyrimidine derivative of the formula (III) can be synthesized according to a method as shown by the following reaction scheme: 
In Step 1, a 3-aminothiophene derivative (II) is reacted with urea to prepare a thienopyrimidine-2,4-dione derivative (III). The reaction can be carried out in the absence of solvents or in the presence of an inert organic solvent such as DMF and DMSO at 0 to 250xc2x0 C.
In Step 2, the thienopyrimidine-2,4-dione derivative (III) is reacted with a halogenating reagent (IV) in the presence of a base to prepare a 2,4-dihalothienopyrimidine derivative (V). As the halogenating reagent, there may be employed phosphorus oxychloride, phosphorus pentachloride or thionyl chloride; while an organic base such as N,N-dimethylaniline, N,N-diethylaniline, triethylamine, pyridine and collidine is employed as the base. The reaction can be carried out in the absence of solvents or in the presence of an inert solvent at 0 to 200xc2x0 C.
In Step 3, the 2,4-dihalothienopyrimidine derivative (V) is reacted with an amine derivative (VI) to prepare a 2-halo-4-aminothienopyrimidine derivative (VII). The reaction can be carried out in an inert solvent such as DMF, THE, dioxane, DMSO and chloroform at a reaction temperature of xe2x88x9278 to 100xc2x0 C. Besides such organic bases, there may be employed an inorganic base such as sodium carbonate, potassium carbonate, sodium methoxide and potassium t-butoxide.
In Step 4, the 2-halo-4-aminothienopyrimidine derivative (VII) is reacted with an amine derivative (VIII) to prepare a thienopyrimidine derivative (I). The reaction can be carried out in the absence of solvents or in the presence of the above-mentioned inert at 0 to 250xc2x0 C. Addition of the organic base or the inorganic base is preferable in order to carry out the reaction efficiently.
Since the pyrimidine nucleus-containing compound of the present invention indicates the excellent PaO2 enhancing actions and very little toxicity, it is useful as a medicament for prophylaxis and therapy of hypoxemia.
The present invention relates also to pharmaceutical compositions containing a compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral, nasal, percutaneous, transcutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets, dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules, etc.
The dosage varies according to the sex, age and weight of the patient, the administration route, the nature of the therapeutic indication, or possible associated treatments, and the ranges from 0.01 mg to 1 g per 24 hours in 1 or more administration.